The present invention relates to fusion proteins for stimulating growth of hematopoietic cells, and more particularly to the construction of fusion proteins comprising MGF and IL-3.
Hematopoietic growth factors (or hematopoietins) regulate the growth and maturation of various lineages of blood cells. All blood cells are believed to develop from a single class of precursor cells called stem cells. Each hematopoietin causes specific classes of blood cells to differentiate and proliferate. When a stem cell divides in the bone marrow, it can replicate itself as a stem cell or become committed to a particular developmental pathway. As a result of commitment to a particular developmental pathway, a stem cell displays receptors on its cell surface that enables it to respond to certain hormonal signals. Such signals push the cell further down a pathway leading to terminal differentiation.
A number of hematopoietins have been identified which regulate cell development at various levels within the hematopoietic stem and progenitor cell hierarchy. The majority of growth factors that have been identified influence relatively late stages of differentiation and regulate the number and function of mature differentiated hematopoietic elements. Interleukin-3 ("IL-3" or "multi-CSF)), for example, stimulates formation of a broad range of hematopoietic cells, including granulocytes, macrophages, eosinophils, mast cells, megakaryocytes and erythroid cells. IL-3 has been identified, isolated and molecularly cloned (EP Publ. Nos. 275,598 and 282,185). Recently, a Mast Cell Growth Factor "MGF"), which controls very early progenitors in the hematopoietic hierarchy, has been identified, isolated and molecularly cloned (Williams et al., Cell 63:167, 1991; Anderson et al., Cell 63:235, 1991).
Preclinical studies indicate that such hematopoietins may be useful in treating various cytopenias, potentiating immune responsiveness to infectious pathogens, and assisting in reconstituting normal blood cell populations following viral infection or radiation or chemotherapy-induced hematopoietic cell suppression. MGF, in particular, because of its early effect on hematopoietic cells, is likely to be useful for treating a plastic anemia. In order to determine their optimal therapeutic potential, the effect of various combinations of such proteins on hematopoietic cells has been the subject of considerable study.